The role that insulin resistance and hyperinsulinemia play in the pathogenesis of hypertension has received much attention in recent years. Although a cause-and-effect relationship between insulin and blood pressure has not been clearly established, hyperinsulinemia exerts several pressor actions that may predispose towards hypertension development. Of the putative prohypertensive actions of insulin, activation of the sympathetic nervous system is the most well established. Thus, infusion of insulin during euglycemic clam elevates plasma norepinephrine and sympathetic nerve activity in humans and in experimental animals. It remains unclear, however, what physiological mechanisms and which sites mediate the excitatory effects of insulin on the sympathetic nervous system. To address these questions, our laboratory recently demonstrated that: 1) acute administration of insulin into the third cerebral ventricle increases sympathetic nerve activity, and 2) destruction of tissues surrounding the anteroventral third ventricle region (AV3V) abolishes elevations in sympathetic activity to systemic insulin. The present research plan will extend these findings by first, identifying specific neural sites that respond to insulin with sympathoexcitation, and second, by examining the chronic effects of third ventricular insulin infusion as well as the chronic effects of AV3V lesions. A determination of which AV3V-related neural sites respond to insulin will be accomplished using selective brain lesions and microinfusion of insulin. Specifically, it will be determined whether lesion of the subfornical organ (SFO), the organum vasculosum of the lamina terminalis (OVLT), or the area postrema (AP) abolish increases in sympathetic activity to systemic insulin. To complement these findings, it will be also determined whether infusion of insulin into the SFO, OVLT, or AP directly elicit elevations in sympathetic outflow. For the chronic studies, we will examine whether long-term third ventricular insulin infusion elevates sympathetic activity and increases blood pressure, and whether AV3V lesions protect against chronic insulin-induced sympathoexcitation and hypertension. Because very little is known about how insulin increases sympathetic activity, the results from these experiments will provide fundamental new information regarding the mechanisms of insulin-induced hypertension. Thus, findings from this research will contribute new knowledge that is of significant relevance to human disease conditions associated with insulin resistance, hyperinsulinemia and hypertension.